Furthermore the in vivo anti inflammatory
Furthermore, the in vivo anti-inflammatory and immunosuppressive effect of ASC was demonstrated by results from animal models. The xylene-induced ear swelling is a common inflammatory model for evaluating vascular permeability. Our studies proved that ASC (50mg/kg) strongly inhibited xylene-induced ear swelling in mice.
HDHODH could be a potential target for development of anti-rejection drugs, since inhibition of hDHODH suppressed lymphocytes activity against specific alloantigen. Several hDHODH inhibitors had been proved to have beneficial effects on rejection and prolong survival time of organ (Rusai et al., 2012, Wennberg et al., 2000). In allogeneic skin graft study, we found that ASC could markedly inhibit skin graft necrosis and increase mean graft survival time.
RA is a chronic SC-514 characterized by painful joints and progression to irreversible joint destruction (McInnes and Schett, 2011). hDHODH is an effective target for RA chemotherapy, as it plays an important role in inflammation and immunoregulation. In the present study, the CIA model was used to investigate the anti-arthritic effect of ASC. Our results showed that 40mg/kg ASC treatment significantly attenuated ankle joint swelling in rats and exhibited sustained anti-arthritis effect over 4 weeks.
In summary, ASC from microbial metabolites was identified as a new structural class of hDHODH inhibitors with in vitro and in vivo effects on anti-inflammation and immunosuppresion. It may be a promising candidate for development of new therapy for the treatment of autoimmune diseases.
Conflicts of interest
Dihydroorotate dehydrogenase (DHODH) is responsible for the conversion of dihydroorotate to orotate, which is the rate-limiting step in pyrimidine biosynthesis. Inhibitors of DHODH show immunosuppressant and antiproliferative activities, which are most pronounced on activated T-cells. Leflunomide, an inhibitor of DHODH, is currently used to treat rheumatoid arthritis, and analogs are in clinic to treat graft versus host disease and multiple sclerosis. A novel series of DHODH inhibitors was developed by us based on a lead that was discovered during a docking procedure and medicinal chemistry exploration. The activity of the initial lead was improved by a QSAR method and yielded low nanomolar inhibitors.
Introduction The most common metabolic hallmark of malignant tumors (i.e., the “Warburg effect”) is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen. Increased glucose uptake usually reflects an increased rate of glycolysis, with conversion of glucose to lactate and decreased utilization of pyruvate for mitochondrial oxidative phosphorylation (OXPHOS) (Liberti and Locasale, 2016, Zong et al., 2016). Since the seminal studies of Otto Warburg one century ago, biochemical research on cancer cell metabolism has revealed the highly metabolic plasticity of cancer cells. A large number of metabolic profiles have been discovered, from the highly glycolytic phenotype repeatedly observed on fast-growing cell lines (Vander Heiden et al., 2009, Ward and Thompson, 2012) to the completely opposite profile characterized by a higher dependency on OXPHOS, as found in metastasis (Porporato et al., 2014) or a subclass of diffuse B cell lymphomas (Caro et al., 2012). It is now widely accepted that OXPHOS and glycolysis cooperate to sustain the energy demands of cancer cells (Smolková et al., 2011, Ward and Thompson, 2012) and that cancer cells undergo metabolic reprogramming to maintain anabolism through various mechanisms including the deviation of glycolysis, Krebs cycle truncation, and OXPHOS redirection toward lipid and protein synthesis (Jose et al., 2011, Pavlova and Thompson, 2016). The critical role of mitochondria in carcinogenesis and gene regulation was further evidenced by recent studies on various oncometabolites produced by the tricarboxylic acid (TCA) cycle (Galluzzi et al., 2013, Ward and Thompson, 2012) and by the role of glutaminolysis, a biochemical pathway located in mitochondria (Villar et al., 2015). A better understanding of what determines tumor bioenergetics is also crucial for developing adapted metabolic therapies, as currently proposed for isocitrate dehydrogenase (IDH) 1 and 2 mutant tumors (Emadi et al., 2014, Seltzer et al., 2010).